Effects of Therapeutic Hypercapnia on Mesenteric Ischemia–Reperfusion Injury

Laffey, John G.; Jankov, Robert P.; Engelberts, Doreen; Tanswell, A. Keith; Post, Martin; Lindsay, Thomas F.; Mullen, J. Brendan; Romaschin, Alex; Stephens, Derek; McKerlie, Colin; Kavanagh, Brian P.

doi:10.1164/rccm.2108078

Cited by 87 publications

(68 citation statements)

References 46 publications

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“…Our findings on Pa O 2 are in keeping with previously reported observations in both rats (19,35) and humans (22,42) indicating that mild-moderate hypercapnia improves systemic oxygenation. Possible mechanisms for an effect of hypercapnia on systemic oxygenation include improved right ventricular performance, as shown in this study, and reduced metabolic activity and O 2 consumption, as reported by others (22,42).…”

Section: Discussionsupporting

confidence: 93%

“…The present study adds to a growing body of experimental evidence (35,36,38,47) indicating that hypercapnia can have beneficial effects on the pulmonary circulation. Whereas there is a relatively large body of literature examining the acute pulmonary vascular effects of hypercapnia (54), we are aware of only one other study (47) where the chronic effects of hypercapnia were examined.…”

Section: Discussionmentioning

confidence: 64%

“…We did not examine for incremental improvements in pulmonary hypertension and vascular remodeling at concentrations Ͼ10% CO 2 , since we anticipated that higher levels would have increased mortality, as our group has reported in adult rats (35). It was not possible in our noninstrumented newborn rat model to separate the effects of acidosis from hypercapnia by chronically buffering pH, which would be required to ascertain the underlying basis for the beneficial effects of chronic hypercapnia.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

Kantores¹,

McNamara²,

Teixeira³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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108

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. Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat. Am J Physiol Lung Cell Mol Physiol 291: L912-L922, 2006. First published July 7, 2006 doi:10.1152/ajplung.00480.2005.-Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at Ͻ0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P Ͻ 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway. carbon dioxide; endothelin; oxidant stress; 8-isoprostane; echocardiography PULMONARY HYPERTENSION, characterized by increased pulmonary artery resistance and pressure, is a common complication of sick newborn infants that carries a high mortality and is associated with considerable long-term morbidity in survivors (43,59,60). Studies suggest that the newborn is uniquely susceptible to remodeling of pulmonary resistance arteries (49). Vascular remodeling contributes to increased resistance (15), may limit the effectiveness of vasodilator therapies (15,32), and in the newborn appears to contribute to inhibition of lung growth and alveolar development (33,45,46,57). Reversal of pathological changes in the newborn pulmonary vascular bed is also more likely to be delayed and incomplete (29,31,49), leading to an increased susceptibility to the development of more severe pulmonary hypertension in later life (10, 17). Thus therapies aimed at preventing or ameliorating vascular remodeling in the newborn have great potential to improve mortality and long-term outcome.A major pathological role for reactive oxygen species (ROS) in pulmonary hypertension is likely, as evidenced by observational studies showing increased oxidant stress in the lungs of adult humans with idiopathic pulmonary arterial hypertension (6, 13) and by the reported efficacy of various antioxidant interventions in the pr...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

Kantores¹,

McNamara²,

Teixeira³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

108

View full text Add to dashboard Cite

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“…11 There is an evolving body of evidence suggesting that hypercapnic acidosis exerts biologically important beneficial effects in experimental models. Laffey et al 12,13 showed that therapeutic hypercapnia was applied to the animals by the deliberated elevation of CO 2 , which also markedly reduced the extent of ischemia-reperfusion injuries. Subsequent studies have demonstrated hypercapnia's protective effects against VILI in both isolated perfused lungs and an animal model.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] The mechanism by which hypercapnic acidosis affects acute lung injury, includes the attenuation of NF-kB activation, 17 the inhibition of endogenous xanthine oxidase 18 and oxygen radical formation, 19 and the reducing release of the cytokines. 12,20,21 However, it is still unclear whether hypercapnic acidosis may affect cell apoptosis and oxidative stress injury of the alveolar by MAPK pathways in VILI.…”

Section: Introductionmentioning

confidence: 99%

Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury

Yang

Song

Wang

et al. 2013

Laboratory Investigation

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Hypercapnic acidosis may attenuate ventilator-induced lung oxidative stress injury and alveolar cell apoptosis, but the underlying mechanisms are poorly understood. We examined the effects of hypercapnic acidosis on the role of apoptosis signal-regulating kinase 1 (ASK1), which activates the c-Jun N-terminal kinase (JNK) and p38 cascade in both apoptosis and oxidative reactions, in high-pressure ventilation stimulated rat lungs. Rats were ventilated with a peak inspiratory pressure (PIP) of 30 cmH 2 O for 4 h and randomly given FiCO 2 to achieve normocapnia (PaCO 2 at 35-45 mm Hg) or hypercapnia (PaCO 2 at 80-100 mm Hg); normally ventilated rats with PIP of 15 cmH 2 O were used as controls. Lung injury was quantified by gas exchange, microvascular leaks, histology, levels of inflammatory cytokines, and pulmonary oxidative reactions. Apoptosis through the ASK1-JNK/p38 mitogen-activated protein kinase (MAPK) cascade in type II alveolar epithelial cells (AECIIs) were evaluated by examination of caspase-3 activation. The results showed that injurious ventilation caused significant lung injury, including deteriorative oxygenation, changes of histology, and the release of inflammatory cytokines. In addition, the high-pressure mechanical stretch also induced apoptosis and caspase-3 activation in the AECIIs. Hypercapnia attenuated these responses, suppressing the ASK1 signal pathways with its downstream kinase phosphorylation of p38 MAPK and JNK, and caspase-3 activation. Thus, hypercapnia can attenuate cell apoptosis and oxidative stress damage in rat lungs during injurious ventilation, at least in part, due to the suppression of the ASK1-JNK/p38 MAPK pathways.

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